RAPLON^TM (rapacuronium bromide) FOR INJECTION SHOULD BE ADMINISTERED IN CAREFULLY ADJUSTED DOSAGE BY OR UNDER THE SUPERVISION OF EXPERIENCED CLINICIANS WHO ARE FAMILIAR WITH THE DRUGS ACTIONS AND THE POSSIBLE COMPLICATIONS OF ITS USE. THE DRUG SHOULD NOT BE ADMINISTERED UNLESS PERSONNEL AND FACILITIES FOR RESUSCITATION AND LIFE SUPPORT (TRACHEAL INTUSATION, ARTIFICIAL VENTILATION, OXYGEN THERAPY). AND AN ANTAGONIST OF RAPLON^TM ARE IMMEDIATELY AVAILABLE. IT IS RECOMMENDED THAT ADEQUATE NEUROMUSCULAR MONITORING EQUIPMENT. SUCH AS A PERIPHERAL NERVE STIMULATOR. BE USED TO MEASURE NEUROMUSCULAR FUNCTION DURING THE ADMINISTRATION OF RAPLON^TM IN ORDERTO MONITOR DRUG EFFECT. DETERMINE THE NEED FOR ADDITIONAL DOSES. AND CONFIRM RECOVERY FROM NEUROMUSCULAR BLOCK.

RAPLON^TM HAS NO KNOWN EFFECT ON CONSCIOUSNESS, PAIN THRESHOLD, OR CEREBRATION, TO AVOID DISTRESS TO THE PATIENT, NEUROMUSCULAR BLOCK SHOULD NOT BE INDUCED BEFORE UNCONSCIOUSNESS. THEREFORE, ADMINISTRATION OF RAPLON^TM MUST BE ACCOMPANIED BY ADEQUATE ANESTHESIA OR SEDATING AGENTS.

Long-Term Use

RAPLON^TM (RAPACURONIUM BROMIDE) FOR INJECTION, SHOULD NOT BE ADMINISTERED BY INFUSION PARTICULARLY IN THE INTENSIVE CARE UNIT (ICU), OR DURING LONG SURGICAL PROCEDURES. In an infusion study (n=90) with RAPLOM^TM, one patient displayed a deterioration of neuromuscular function after attaining evidence of adequate spontaneous recovery. Six minutes after spontaneously recovering to a T₀/T₂ of 70%, the T₄/T₁ decreased to 64%. Thirteen minutes later T₄/T₁ recovered to 80%. This patient did not receive neostigmine and had no respiratory problems that required reintubation or mask assisted breathing.

Radioisotope studies have demonstrated that only 56% of the original Raplon dose had been excreted two weeks following a single IV bolus. Excretion of ¹⁴C-labeled rapacuronium continued for at least six weeks. Accumulation of rapacuronium bromide following repeat dosing is likely to occur but has not been studied.

ECG abnormalities have been observed in animals following repeat doses and large single doses of rapacuronium bromide (See CLINICAL PHARMACOLOGY, Hemodynamics).

During pregnancy there is passage or low levels or rapacuronium across the placenta and slow elimination following a single maternal dose (see CLINICAL PHARMACOLOGY, PHARMACOKINETICS). The risk to the developing fetus from extended low-dose intrauterine exposure to a neuromuscular blocking agent is unknown. Because of these concerns and because animal reproduction studies are not always predictive of human response, this drug should not be used during pregnancy unless the potential benefit to the patient outweighs the potential risk to the fetus. This warning does not extend to use of RAPLON^TM during Cesarean section, but appropriate monitoring of the infant is recommended after delivery (see CLINICAL PHARMACOLOGY, Clinical studies).

In patients with myasthenia gravis or myasthenic (Eaton-Lambert) syndrome, small doses of nondepolarizing neuromuscular blocking agents may have profound effects. In such patients, a peripheral nerve stimulator and use of a small test dose may be of value in monitoring the response to administration of muscle relaxants.

Reconstituted RAPLON^TM, which has an acid pH of 4.0, should not be mixed with alkaline solutions (e.g., barbiturate solutions) in the same syringe or administered simultaneously during

Intravenous infusion through the same needle.

Repeat Dosing

It is strongly recommended that during administration of RAPLON^TM, neuromuscular transmission and recovery be monitored continuously using a nerve stimulator. Additional doses of Raplon^TM should not be given until there is a definite response (one twitch of the train-of-four) to nerve stimulation.

Repeat dosing in adults after intubating doses greater than 1.5 mg/kg, and repeat dosing in pediatric patients have not been studied, and are, therefore, not recommended.

The experience with a limited number of patients indicates that repeat bolus dosing of Raplon^TM may have a potential for prolonged block. Theoretically, increased histamine effects may result from slow elimination of the drug from the body; however, no studies to date have been conducted to substantiate this possibility (see CLINICAL PHARMACOLOGY, Pharmacokinetics).

In three European studies, adult patients were given an intubating dose of 1.5 mg/kg of Raplon^TM (rapacuronium bromide) for injection followed by three maintenance doses of Raplon^TM 0.5 mg/kg (n=61) or 0.55 mg/kg (n=19). In one study, median (range) clinical durations of the three doses of 0.55 mg/kg were 6 (3-12), 8 (5-12), and 8 (5-13) minutes. In the second study, the three maintenance doses of 0.5 mg/kg had median (range) clinical durations of 12 (6-19), 14 (6-22), and 15 (6-35) minutes. Neostigmine was administered to half the patients in this study after the third dose when T1 returned to 25%, and the median (range) time to recover to 70% T4/T1 was 6 (2-9) minutes (n=14). The remaining half of the patients had spontaneous recovery after the third dose. The median spontaneous recovery from 25% T1 to 70% T4/T1 was 57 minutes and ranged from 44 to 80 minutes (n=11). In the third study, the median (range) clinical durations of the first and second maintenance doses of 0.5 mg/kg were 13 (7-20) and 14 (8-29) minutes. Neostigmine (n=12) or edrophonium (n=13) were administered two minutes after the third dose of Raplon. Median (range) time to 70% T4/T1 was 14 (7-24) minutes after neostigmine and 33 (19- 49) minutes after edrophonium (see CLINICAL PHARMACOLOGY, Repeat Dosing in Adults).

In the 80 patients who received three maintenance doses following a bolus dose of 1.5 mg/kg of Raplon^TM, adverse events reported in separate patients during or following the maintenance doses consisted of hypotension, tachycardia, respiratory depression, and bronchospasm.

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